ABSTRACT Shift workers represent nearly 20 % of the US working population, and this occupational hazard conveys increased risk for myriad of pathologies. Our preclinical research provides insight into the basis of shift-work disease. In our previous work, we have revealed that dysregulated inflammation occurs in animal models of shift work, with broad suppression under basal conditions and hypersensitivity to inflammatory challenge. Since aberrant inflammatory responses would be expected to increase stroke, myocardial infarction, diabetes, and cancer, as is observed in shift work epidemiological studies, we hypothesize that chronic dysregulation of inflammation due to environmental disruption underlies the increased risk of disease in career shift workers. In this application, we will conduct a cross-sectional pilot study of human day workers and shift workers exposed to temporally changing occupational environments. We aim to test the hypothesis that humans exposed to shift-work environments develop 1), decreased expression of immune markers, and 2), aberrant inflammatory responses upon ex-vivo endotoxin activation. Furthermore, we will measure individual light exposure parameters, activity/rest changes and expression of stress and metabolic hormones to link a comprehensive immune profile to specific shift-work exposure history. Our initial goal is to uncover aberrant inflammatory responses defined as those in which the critical balance between pro- and anti- inflammatory signaling processes is disrupted and then determine if the severity of disruption relates to increased shift-work exposure. Long term, our ultimately goal is to establish a preventive medicine research program that will investigate inflammatory responses in actual shift workers using a low-invasive, blood based ex-vivo assay. Follow-up longitudinal studies will develop this assay into a diagnostic tool to identify biological markers linked to the duration of shift-work exposure and to basal biological changes predictive of disease risk. Identification of biological markers of shift-work related environmental disruption may reveal a mechanistic link between shift-work exposure and disease risk, and may become a future tool for workplace intervention by preventive identification of aberrant inflammatory responses in specific shift scheduling systems. .